Activation of Aldehyde Dehydrogenase 2 Ameliorates Glucolipotoxicity of Pancreatic Beta Cells

• Published in: Biomolecules (Basel, Switzerland) Vol. 11; no. 10; p. 1474
• Main Authors: Chen, Shiau-Mei, Hee, Siow-Wey, Chou, Shih-Yun, Liu, Meng-Wei, Chen, Che-Hong, Mochly-Rosen, Daria, Chang, Tien-Jyun, Chuang, Lee-Ming
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 06.10.2021; MDPI
• Subjects: 4-Hydroxynonenal; Adenosine Triphosphate - genetics; Alda-1; Aldehyde dehydrogenase; aldehyde dehydrogenase 2 (ALDH2); Aldehyde Dehydrogenase, Mitochondrial - genetics; Aldehydes - pharmacology; Animals; Apoptosis; Apoptosis - drug effects; Benzamides - pharmacology; Benzodioxoles - pharmacology; beta cell function; Beta cells; Cell death; Cell Death - drug effects; Cell viability; Dehydrogenases; Disease Models, Animal; Experiments; Fatty acids; Gene expression; glucolipotoxicity; Glucose; Glucose - metabolism; Humans; Hyperglycemia; Hyperlipidemia; Insulin; Insulin resistance; Insulin secretion; Insulin Secretion - genetics; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - pathology; Intracellular; Lipids; Lipids - genetics; Metabolic Detoxication, Phase I - genetics; Mitochondria; Mitochondria - drug effects; Mitochondria - genetics; Mitochondria - metabolism; Oxidative stress; Oxidative Stress - drug effects; Oxygen consumption; Pancreas; Pyruvaldehyde; Reactive oxygen species; Reactive Oxygen Species - metabolism; Secretion; Sweden; United States > US; Germany; Taiwan; aldehyde dehydrogenase 2 (ALDH2); glucolipotoxicity; beta cell function; Alda-1
• ISSN: 2218-273X; 2218-273X
• DOI: 10.3390/biom11101474

Chronic hyperglycemia and hyperlipidemia hamper beta cell function, leading to glucolipotoxicity. Mitochondrial aldehyde dehydrogenase 2 (ALDH2) detoxifies reactive aldehydes, such as methylglyoxal (MG) and 4-hydroxynonenal (4-HNE), derived from glucose and lipids, respectively. We aimed to investigate whether ALDH2 activators ameliorated beta cell dysfunction and apoptosis induced by glucolipotoxicity, and its potential mechanisms of action. Glucose-stimulated insulin secretion (GSIS) in MIN6 cells and insulin secretion from isolated islets in perifusion experiments were measured. The intracellular ATP concentrations and oxygen consumption rates of MIN6 cells were assessed. Furthermore, the cell viability, apoptosis, and mitochondrial and intracellular reactive oxygen species (ROS) levels were determined. Additionally, the pro-apoptotic, apoptotic, and anti-apoptotic signaling pathways were investigated. We found that Alda-1 enhanced GSIS by improving the mitochondrial function of pancreatic beta cells. Alda-1 rescued MIN6 cells from MG- and 4-HNE-induced beta cell death, apoptosis, mitochondrial dysfunction, and ROS production. However, the above effects of Alda-1 were abolished in Aldh2 knockdown MIN6 cells. In conclusion, we reported that the activator of ALDH2 not only enhanced GSIS, but also ameliorated the glucolipotoxicity of beta cells by reducing both the mitochondrial and intracellular ROS levels, thereby improving mitochondrial function, restoring beta cell function, and protecting beta cells from apoptosis and death.